CN117683022A

CN117683022A - An amide compound and its preparation method and application

Info

Publication number: CN117683022A
Application number: CN202311703321.3A
Authority: CN
Inventors: 戴大鹏; 王双虎; 高瑞娟; 杨航; 蔡剑平; 綦钰莹
Original assignee: Beijing Hospital
Current assignee: Beijing Hospital
Priority date: 2023-12-12
Filing date: 2023-12-12
Publication date: 2024-03-12

Abstract

The invention relates to an amide compound, the chemical structure of which is shown as the following formula (I)A is selected from-CH ₂ ‑、X is selected from-CH-, -NH-; l is selected from B is selected from R ₁ Selected from H, amino, hydroxy, cyano, halogen; r is R ₂ Selected from H, amino, hydroxy, cyano, halogen. The amide compound disclosed by the invention can be used for degrading BDR4 and GSPT1 simultaneously, and has a very good killing effect on blood system tumor cells (including multiple myeloma, lymphoma and leukemia), and is better than clinical candidate medicine CC-90009.

Description

Amide compound and preparation method and application thereof

Technical Field

The invention relates to the technical field of compounds, in particular to an amide compound, a preparation method and application thereof.

Background

Leukemia, malignant lymphoma, and multiple myeloma are three major malignancies of the blood system. Thanks to the general application of the novel targeted drugs, the 5-year survival rate of various kinds of hematological tumors is significantly improved by more than 20% compared with 50 years ago, but on the other hand, the survival rate of Acute Myeloid Leukemia (AML) patients is still at a relatively minimum level. The existing tumor targeting drugs for NHL and AML reduce the side effects of the drugs to a certain extent, but the drug resistance is easy to occur, and meanwhile, most of the drugs are developed by foreign institutions, and have the disadvantages of overhigh part of drug cost, heavy patient burden and lack of drugs developed locally.

The G1 to S phase transition 1 gene (G1 to S phase transition, GSPT1) was originally identified as the gene necessary for the G1 phase transition to S phase in the cell cycle and was later more named eukaryotic peptide chain releasing factor 3a (eRF 3 a). The eRF3a as a key member in peptide chain release factor is involved in a variety of biological processes including termination of protein translation, modulation of intracellular mRNA degradation, modulation of cell growth cycle and apoptosis, participation in cytoskeletal formation, and the like. GSPT1 dysfunction is closely related to the occurrence and progression of various common malignancies, such as NHL and AML. CC-90009 is the first clinical candidate drug specifically aiming at GSPT1 degradation, and is the phase I clinical candidate drug for treating acute leukemia AML (NCT 04336982) and myelodysplastic syndrome MDS (NCT 02848001), but the CC-90009 has a single structure, and the inhibition effect on blood system tumors is still to be improved.

BRD4, an epigenetic regulator and transcription cofactor, is closely related to gene transcription, cell cycle and apoptosis, invasion and metastasis. The abnormal expression of BRD4 can cause the imbalance of the expression of various genes, affect the functions of related genes, and play an important role in the processes of tumorigenesis, development, infiltration, metastasis of tumor cells and the like. The BRD4 inhibitor shows good anti-tumor effect and has good application prospect in various tumors, especially blood system tumors. However, whether the compound is a BRD4 inhibitor or a GSPT1 PROTAC molecule, a better treatment effect on refractory NHL and AML is difficult to achieve, and in order to break through the difficult problem, the applicant discovers that the designed compound can degrade BRD4 and GSPT1 simultaneously through scientific research, so that the killing effect of the compound on NHL and AML tumor cells can be obviously enhanced. At present, no compound can degrade BRD4 and GSPT1 at the same time, and both are difficult to achieve. The compound which can degrade BRD4 and GSPT1 simultaneously is developed and used for treating NHL and AML tumor patients, and has important research significance and wide clinical application early stage.

Disclosure of Invention

The inventor discovers through research that the designed compound can degrade BRD4 and GSPT1 simultaneously, and shows stronger inhibition activity than clinical phase II medicine CC-90009. The invention aims to provide a difunctional compound for simultaneously degrading BDR4 and GSPT1 proteins, a preparation method and application thereof, wherein the compound has the advantages of high activity, low toxic and side effects and the like when being used as a difunctional degradation agent for BRD4 and GSPT1 proteins.

In a first aspect, the present invention provides an amide compound.

Specifically, an amide compound has a molecular structure shown in the following formula (I):

wherein A is selected from-CH ₂ -、X is selected from-CH-, -NH-; l is selected from->

B is selected from-> R ₁ Selected from H, amino, hydroxy, cyano, halogen; r is R ₂ Selected from H, amino, hydroxy, cyano, halogen.

Preferably, the glutarimide compound is characterized by having any one of the following structural formulas Ia and Ib:

wherein X is selected from-CH-, -NH-; l is selected from

B is selected fromR ₁ Selected from H, amino, hydroxy, cyano, halogen; r is R ₂ Selected from H, amino, hydroxy, cyano, halogen.

Further preferably, the glutarimide compound has any one of the following structural formulas 1 to 18:

the second aspect of the present invention provides a method for preparing an amide compound, comprising the steps of:

carrying out condensation reaction on a compound shown in a formula (II) and a compound shown in a formula (III) under the conditions of 4- (4, 6-dimethoxy triazine-2-yl) -4-methylmorpholinium chloride and azomethylmorpholine to obtain a compound shown in a formula (1):

wherein X is selected from-CH-, -NH-; l is selected from

B is selected fromR ₁ Selected from H, amino, hydroxy, cyano, halogen; r is R ₂ Selected from H, amino, hydroxy, cyano, halogen, n is equal to 1 or 2.

The temperature of the condensation reaction is 20-30 ℃, the time is 0.5-3 hours, the amount of 4- (4, 6-dimethoxy triazine-2-yl) -4-methyl morpholinium chloride is 1.5 equivalent, the amount of nitrogen methyl morpholine is 2 equivalent, and the solvent is DMF.

In a third aspect, the invention also relates to a pharmaceutical composition comprising a compound as described hereinbefore or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt, solvate, polymorph or oxynitride thereof in a physiologically acceptable medium. Preferably, the medicament further comprises a pharmaceutically acceptable carrier and an auxiliary material.

In a fourth aspect, the invention also relates to the use of a compound as described hereinbefore or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt, solvate, polymorph or oxynitride thereof, said pharmaceutical composition for the preparation of a medicament for BRD4 degradation or GSPT1 degradation.

In a fifth aspect, the invention also relates to the use of a compound as described hereinbefore or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt, solvate, polymorph or oxynitride thereof, said pharmaceutical composition for the manufacture of a medicament for the treatment of a neoplastic disease associated with BRD4 and GSPT1 targets. Preferably, the neoplastic disease includes non-hodgkin's lymphoma, chronic lymphocytic leukemia, B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia.

Compared with the prior art, the invention has the following beneficial effects:

the amide compound provided by the invention has a molecular structure shown in a formula (I), can obviously degrade BRD4 and GSPT1, is a BRD4/GSPT1 double-target degradation compound, has an obvious effect, and shows stronger inhibition activity than a clinical phase I drug CC-90009. Therefore, the amide compound provided by the invention has good application prospect in the treatment of blood system tumors.

Detailed Description

In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples will be presented. It should be noted that the following examples do not limit the scope of the invention.

The starting materials, reagents or apparatus used in the following examples are all available from conventional commercial sources or may be obtained by methods known in the art unless otherwise specified.

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The room temperature described in the examples is room temperature conventional in the art, preferably 20-30 ℃.

The progress of the reaction according to the invention is monitored by conventional monitoring methods, such as TLC (thin layer chromatography), LCMS (liquid chromatography) or NMR (nuclear magnetic resonance), generally by taking the reaction substrate as the end point when it disappears.

In the following specific examples, the liquid chromatography conditions used for detection and identification of the prepared compounds were: island LCMS2020, G1322A degasser, G1312 binary high pressure pump, G1329A autosampler, G1316A column oven, G4212B diode array detector. The column was Xbridge C18 (50 mm. Times.4.6 mm,5.0 μm) and was eluted with a gradient of deionized water as mobile phase A and acetonitrile containing 0.1% trifluoroacetic acid as mobile phase B, with the following procedure:

time (min)	Mobile phase a (volume%)	Mobile phase B (volume%)
			0.01	95	5
1.50	95	5
			3.00	5	95
3.50	5	95
			4.00	95	5
5.00	95	5

The flow rate was 1.5mL/min, the column temperature was 40℃and the detection wavelength was 254nm.

Terminology

Unless otherwise indicated, the following terms appearing in the present specification and claims have the following meanings:

the invention also relates to useful forms of the compounds disclosed herein, e.g., metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and co-precipitates.

Further, the compounds of the present invention may exist in free form, e.g., as a free base or free acid or zwitterionic, or may exist in salt form. The salt may be any salt commonly used in pharmacy, organic or inorganic addition salts, in particular any pharmaceutically acceptable organic or inorganic addition salt.

Pharmaceutically acceptable salts of the compounds of the invention may be, for example, acid addition salts of the compounds of the invention which carry a nitrogen atom in the chain or ring, for example, acid addition salts of the compounds of the invention which are sufficiently basic, for example, acid addition salts with inorganic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid, or acid addition salts with organic acids, for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) -benzoic acid, camphoric acid, cinnamic acid, cyclopentanoic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectate acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, gluconic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

The compounds of the invention may contain non-natural proportion isotopes on one or more of the atoms making up the compound, for example substitution of hydrogen with deuterium to form deuterated drugs.

As used herein, the term "stereoisomer" refers to a compound having the same chemical constitution but differing in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers and the like.

As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

As used herein, the term "diastereoisomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated by chiral HPLC.

The drug sensitivity experiment is adopted to detect the inhibition of the compound on the activity of NHL and AML tumor cells, and the WB experiment is adopted to detect the degradation effect of the compound on GSPT1 and BRD4, so that the result shows that the compound has good killing effect on NHL and AML tumor cells, can efficiently degrade GSPT1 and BRD4, and is superior to clinical candidate drug CC-90009.

It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and thus two or more stereoisomers may be present. Thus, the compounds of the invention may exist as individual stereoisomers (e.g. enantiomers, diastereomers) and mixtures thereof in any proportion, e.g. racemates, and, where appropriate, as tautomers and geometric isomers thereof.

Example 1

The specific operation method of the amide compound route of the invention is as follows, and the target product is synthesized through the route 1

Route 1:

the compound represented by the formula (II) was condensed with the compound represented by the formula (III) (II: III equivalent ratio=1:1) under the conditions of 4- (4, 6-dimethoxytriazin-2-yl) -4-methylmorpholinium chloride (1.5 equivalent), azomethylmorpholine (2 equivalent), DMF (20 equivalent). The condensation reaction temperature is 20-30 ℃, the time is 0.5-3 hours, the 4- (4, 6-dimethoxy triazine-2-yl) -4-methyl morpholinium chloride is 1.5 equivalent, the nitrogen methyl morpholine is 2 equivalent, and the solvent is DMF. After completion of LCMS monitoring, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phase was washed 3 times with brine, dried over anhydrous sodium sulfate, and Prep-TLC purified to give the final product, target compounds 1-20.

The identification result of the target compound 1 is as follows:

4-(4-(1-(2-(4-chlorophenyl)-2,2-difluoroacetyl)piperidin-4-yl)piperazin-1-yl)-2-(2,6-di oxopiperidin-3-yl)isoindoline-1,3-dione(1). ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),7.73-7.68(m,1H),7.65(d,J＝8.5Hz,2H),7.59(d,J＝8.6Hz,2H),7.34(dd,J＝15.3,7.8Hz,2H),5.09(dd,J＝12.7,5.4Hz,1H),4.39(d,J＝12.3Hz,1H),3.75(d,J＝13.0Hz,1H),3.29(s,5H),3.02(d,J＝12.7Hz,1H),2.86(d,J＝16.3Hz,2H),2.75-2.54(m,5H),2.06-2.00(m,1H),1.91(s,1H),1.72(s,1H),1.38(s,2H),1.08(s,2H). ¹³ C NMR(101MHz,DMSO)δ173.32,170.38,167.55,166.95,166.66,136.45,136.30,134.04,129.85,129.59,127.47,124.10,117.03,115.56,60.45,50.94,49.20,48.91,44.72,42.62,31.43,22.46.

the preparation method of the glutarimide compound 2-20 is the same as the preparation method of the compound 1. The identification results of the target product 2 20 are respectively as follows:

4-(4-((1-(2-(4-chlorophenyl)-2,2-difluoroacetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(2). ¹ H NMR(400MHz,DMSO)δ11.08(s,1H),7.71(t,J＝7.7Hz,1H),7.64(d,J＝8.5Hz,2H),7.58(d,J＝8.5Hz,2H),7.40-7.32(m,2H),5.09(dd,J＝12.7,5.4Hz,1H),4.35(d,J＝12.5Hz,1H),3.71(d,J＝13.5Hz,2H),2.98(s,1H),2.94-2.73(m,5H),2.69-2.52(m,4H),2.18(s,2H),2.10-1.94(m,2H),1.83(s,2H),1.64(s,2H),1.06(s,1H),0.76(s,1H). ¹³ C NMR(101MHz,DMSO)δ173.32,170.31,167.40,166.82,162.74,160.46,137.86,136.44,134.13,132.52,129.72,127.30,124.13,115.53,104.79,67.77,52.97,49.12,45.66,43.19,36.26,31.62,31.35,30.56,29.94,29.37,22.41.

4-(4-((4-(2-(4-chlorophenyl)-2,2-difluoroacetyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(3). ¹ H NMR(400MHz,DMSO)δ11.08(s,1H),7.65(dd,J＝7.8,5.6Hz,3H),7.58(d,J＝8.6Hz,2H),7.31(dd,J＝7.8,3.3Hz,2H),5.08(dd,J＝12.8,5.4Hz,1H),3.73-3.53(m,5H),2.84(t,J＝11.4Hz,3H),2.61-2.49(m,4H),2.16(d,J＝6.7Hz,4H),2.05-1.99(m,1H),1.78(d,J＝11.5Hz,2H),1.67(s,1H),1.28(dd,J＝23.8,12.2Hz,3H). ¹³ C NMR(101MHz,DMSO)δ173.23,170.43,167.50,166.68,160.65,150.55,136.47,136.14,134.07,132.35,129.71,127.48,124.31,116.65,115.49,114.74,63.72,53.22,52.91,51.32,49.16,45.99,43.26,32.46,31.35,30.73,22.48.

4-(4-(4-(2-(4-chlorophenyl)-2,2-difluoroacetyl)piperazin-1-yl)piperidin-1-yl)-2-(2,6-di oxopiperidin-3-yl)isoindoline-1,3-dione(4). ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),7.65(dd,J＝16.8,8.4Hz,3H),7.57(d,J＝8.6Hz,2H),7.34-7.27(m,2H),5.06(dd,J＝12.7,5.5Hz,1H),3.70(d,J＝11.8Hz,2H),3.37(s,2H),3.16(d,J＝4.1Hz,1H),2.83(t,J＝11.5Hz,3H),2.62-2.44(m,6H),2.35(s,2H),2.01(dd,J＝8.8,3.7Hz,1H),1.81(d,J＝10.9Hz,2H),1.63-1.48(m,2H). ¹³ C NMR(101MHz,DMSO)δ173.32,170.45,167.52,166.70,162.90,150.12,136.50,136.23,133.95,129.70,127.47,124.36,116.69,115.00,60.66,50.65,49.16,48.98,48.57,36.25,31.22,28.06,22.45.

4-(4-((1-(2-(4-chlorophenyl)-2,2-difluoroacetyl)azetidin-3-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(5). ¹ H NMR(400MHz,DMSO)δ11.08(s,1H),7.73-7.68(m,1H),7.62(s,4H),7.35(dd,J＝12.3,7.8Hz,2H),5.09(dd,J＝12.7,5.4Hz,1H),4.43(t,J＝8.8Hz,1H),4.09(t,J＝9.3Hz,1H),4.01(d,J＝8.1Hz,1H),3.68(dd,J＝10.1,5.6Hz,1H),3.27(s,4H),2.95-2.85(m,2H),2.63-2.53(m,8H),2.05-1.99(m,1H). ¹³ C NMR(101 MHz,DMSO)δ179.00,172.88,170.07,166.97,163.54,150.13,143.78,141.98,136.63,134.17,129.75,127.91,121.80,116.68,60.05,56.86,56.56,53.60,52.77,50.73,49.16,32.39,31.62,26.90,22.20.

4-(4-((1-(4,6-dimethoxy-1,3,5-triazin-2-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(6). ¹ H NMR(400 MHz,DMSO)δ11.09(s,1H),7.71(t,J＝7.8Hz,1H),7.62(d,J＝4.7Hz,1H),7.36(s,1H),5.10(dd,J＝12.8,5.4Hz,1H),4.17(t,J＝8.8Hz,2H),3.79(d,J＝25.6Hz,12H),3.02-2.84(m,3H),2.60(d,J＝18.1Hz,7H),2.06-1.99(m,1H). ¹³ C NMR(101 MHz,DMSO)δ173.21,172.06,170.39,167.45,167.23,166.72,136.32,134.03,129.43,124.17,117.07,115.35,54.53,53.87,52.88,49.21,31.35,27.04,22.45.

5-(4-(1-(2-(4-chlorophenyl)-2,2-difluoroacetyl)piperidin-4-yl)piperazin-1-yl)-2-(2,6-di oxopiperidin-3-yl)isoindoline-1,3-dione(7). ¹ H NMR(400 MHz,DMSO)δ11.08(s,1H),7.66(dd,J＝10.6,8.8Hz,3H),7.59(d,J＝8.5Hz,2H),7.32(s,1H),7.25(d,J＝8.6Hz,1H),5.07(dd,J＝12.9,5.3Hz,1H),4.38(d,J＝11.3Hz,1H),3.75(d,J＝12.8Hz,1H),3.07-2.92(m,2H),2.82(d,J＝14.8Hz,2H),2.65-2.51(m,8H),2.02(d,J＝10.7Hz,1H),1.87(s,1H),1.73(s,1H),1.36(s,1H),1.23(s,2H),1.05(s,1H). ¹³ C NMR(101 MHz,DMSO)δ173.25,170.69,168.30,167.14,160.52,155.54,153.26,147.41,144.06,140.16,136.28,134.42,129.73,127.32,125.29,118.32,108.29,48.88,48.40,31.37,22.47.

5-(4-((1-(2-(4-chlorophenyl)-2,2-difluoroacetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(8). ¹ H NMR(400 MHz,DMSO)δ11.08(s,1H),7.66(dd,J＝13.8,8.6Hz,3H),7.58(d,J＝8.6Hz,2H),7.33(s,1H),7.25(d,J＝7.8Hz,1H),5.07(dd,J＝12.9,5.3Hz,1H),4.35(d,J＝12.4Hz,1H),3.71(d,J＝13.0Hz,2H),3.03-2.78(m,5H),2.60(s,2H),2.45(s,4H),2.13(s,2H),2.02(d,J＝5.1Hz,1H),1.82(s,2H),1.62(s,1H),1.23(s,2H),1.04(s,1H),0.75(s,1H). ¹³ C NMR(101 MHz,DMSO)δ173.32,170.75,168.01,167.50,167.38,165.17,157.92,145.34,137.56,134.20,129.72,127.44,125.39,116.95,106.31,72.25,58.92,48.93,43.12,31.24,22.49,15.30.

5-(4-(1-(2-(4-chlorophenyl)-2,2-difluoroacetyl)azetidin-3-yl)piperazin-1-yl)-2-(2,6-di oxopiperidin-3-yl)isoindoline-1,3-dione(9). ¹ H NMR(400 MHz,DMSO)δ11.08(s,1H),7.68(d,J＝8.5Hz,1H),7.62(s,4H),7.35(s,1H),7.30-7.24(m,1H),5.07(dd,J＝12.9,5.3Hz,1H),4.41(t,J＝8.2Hz,1H),4.22(d,J＝4.9Hz,1H),4.11-4.04(m,1H),3.88(dd,J＝10.4,4.7Hz,1H),3.45(s,4H),3.23(d,J＝5.3Hz,1H),2.89(dd,J＝18.0,13.5Hz,1H),2.63-2.53(m,2H),2.45(s,4H),2.06-1.98(m,1H). ¹³ C NMR(101 MHz,DMSO)δ173.27,170.47,168.07,167.28,155.64,136.39,134.34,129.41,127.91,125.32,118.76,118.32,115.49,108.48,56.38,54.19,52.95,49.23,48.91,46.96,31.43,22.57.

5-(4-((1-(2-(4-chlorophenyl)-2,2-difluoroacetyl)azetidin-3-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(10). ¹ H NMR(400 MHz,DMSO)δ11.08(s,1H),7.68(d,J＝8.5Hz,1H),7.63(d,J＝9.5Hz,4H),7.33(s,1H),7.25(d,J＝8.6Hz,1H),5.07(dd,J＝12.9,5.3Hz,1H),4.42(t,J＝8.7Hz,1H),4.07(dd,J＝23.1,13.9Hz,2H),3.82-3.51(m,4H),2.98-2.78(m,3H),2.66-2.52(m,6H),2.06-1.99(m,1H),1.23(s,2H). ¹³ C NMR(101 MHz,DMSO)δ173.27,170.71,168.13,167.11,155.53,136.56,134.12,129.48,127.52,125.36,118.32,108.37,56.82,53.21,52.38,49.17,47.24,31.37,22.71.

5-(3-(4-(2-(4-chlorophenyl)-2,2-difluoroacetyl)piperazin-1-yl)azetidin-1-yl)-2-(2,6-di oxopiperidin-3-yl)isoindoline-1,3-dione(11). ¹ H NMR(400 MHz,DMSO)δ11.07(s,1H),7.62(dd,J＝22.0,8.4Hz,5H),6.77(d,J＝1.6Hz,1H),6.64(dd,J＝8.4,1.8Hz,1H),5.05(dd,J＝12.9,5.3Hz,1H),4.07(t,J＝7.8Hz,2H),3.83(dd,J＝8.5,4.9Hz,2H),3.62(s,2H),2.90-2.84(m,1H),2.60(s,3H),2.41(s,2H),2.20(s,2H),2.05-1.99(m,1H),1.23(s,2H). ¹³ C NMR(101 MHz,DMSO)δ173.23,170.38,167.93,167.55,155.17,136.51,134.14,129.81,127.64,125.38,117.36,114.73,104.84,55.27,54.14,49.02,42.74,31.12,26.31,22.59.

5-(3-((4-(2-(4-chlorophenyl)-2,2-difluoroacetyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(12). ¹ H NMR(400 MHz,DMSO)δ10.99(s,1H),7.65-7.55(m,5H),7.46(s,1H),7.06(d,J＝8.5Hz,1H),6.93(d,J＝8.3Hz,1H),5.03(dd,J＝12.7,5.1Hz,1H),4.50-4.10(m,1H),3.77(d,J＝3.7Hz,2H),3.63(s,3H),3.25(d,J＝4.3Hz,2H),2.90(dd,J＝22.1,8.5Hz,1H),2.58(d,J＝17.2Hz,1H),2.35(dd,J＝27.5,21.8Hz,4H),2.21(s,3H),2.05-1.98(m,1H). ¹³ C NMR(101 MHz,DMSO)δ173.34,170.56,168.21,167.61,154.95,136.40,134.56,129.56,127.62,125.66,116.51,57.58,53.25,49.04,46.49,43.35,42.71,37.39,31.40,22.64.

5-(4-((4-(2-(4-chlorophenyl)-2,2-difluoroacetyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(13). ¹ H NMR(400 MHz,DMSO)δ11.07(s,1H),7.61(dd,J＝24.6,8.4Hz,5H),7.28(s,1H),7.21(d,J＝8.7Hz,1H),5.06(dd,J＝12.9,5.3Hz,1H),4.01(d,J＝12.8Hz,2H),3.58(s,2H),3.17(s,1H),2.91(dd,J＝27.4,13.5Hz,3H),2.76-2.52(m,2H),2.36(s,2H),2.29-1.82(m,6H),1.76(d,J＝11.3Hz,3H),1.11(d,J＝11.5Hz,2H). ¹³ C NMR(101 MHz,DMSO)δ173.21,170.50,168.10,167.36,160.55,155.17,136.40,134.15,129.71,127.74,125.66,118.08,117.75,108.11,63.66,52.89,49.22,47.59,43.19,32.56,31.38,29.83,22.59.

5-(4-(4-(2-(4-chlorophenyl)-2,2-difluoroacetyl)piperazin-1-yl)piperidin-1-yl)-2-(2,6-di oxopiperidin-3-yl)isoindoline-1,3-dione(14). ¹ H NMR(400 MHz,DMSO)δ11.07(s,1H),7.62(dt,J＝26.3,6.6Hz,5H),7.31(s,1H),7.24(d,J＝8.6Hz,1H),5.06(dd,J＝13.0,5.3Hz,1H),4.05(d,J＝12.6Hz,2H),3.56(s,3H),3.00-2.85(m,3H),2.59(d,J＝16.2Hz,3H),2.30(s,3H),2.02(s,1H),1.78(d,J＝11.9Hz,2H),1.40(dd,J＝25.4,13.2Hz,2H),1.32-1.22(m,2H). ¹³ C NMR(101 MHz,DMSO)δ173.29,170.59,168.31,167.57,155.01,134.30,129.63,127.66,125.24,117.99,108.20,62.26,60.61,49.14,47.06,37.55,31.85,27.39,22.76.

4-(tert-butyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzamide(15). ¹ H NMR(400 MHz,DMSO)δ11.00(s,1H),9.18(t,J＝5.8Hz,1H),7.87(d,J＝8.4Hz,2H),7.69(d,J＝7.8Hz,1H),7.49(dd,J＝19.9,11.4Hz,4H),5.11(dd,J＝13.3,5.1Hz,1H),4.59(d,J＝5.9Hz,2H),4.44(d,J＝17.4Hz,1H),4.30(d,J＝17.4Hz,1H),2.99-2.84(m,1H),2.60(dd,J＝15.4,2.1Hz,1H),2.38(dd,J＝13.1,4.4Hz,1H),2.00(dd,J＝9.0,3.6Hz,1H),1.30(s,9H). ¹³ C NMR(101 MHz,DMSO)δ173.33,171.44,168.40,166.57,154.54,144.57,142.78,131.78,130.70,127.57,127.42,125.50,123.32,122.40,51.98,47.54,43.03,35.01,31.60,31.33,22.90.

(E)-3-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)a crylamide(16). ¹ H NMR(400 MHz,DMSO)δ11.00(s,1H),8.97(t,J＝5.7Hz,1H),7.69(d,J＝7.8Hz,1H),7.61(d,J＝8.5Hz,2H),7.54-7.42(m,5H),6.79(d,J＝15.8Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.48(dd,J＝27.4,11.7Hz,3H),4.31(d,J＝17.4Hz,1H),2.96-2.87(m,1H),2.63-2.57(m,1H),2.43-2.35(m,1H),2.03-1.97(m,1H). ¹³ C NMR(101 MHz,DMSO)δ173.33,171.43,168.35,165.34,144.14,142.82,138.10,134.23,130.80,129.68,129.38,127.58,123.38,123.21,122.58,51.99,47.55,42.71,31.60,22.89.

N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-phenylpropiolamide(17). ¹ H NMR(400 MHz,DMSO)δ11.02(s,1H),9.51(t,J＝6.0Hz,1H),7.72(d,J＝7.8Hz,1H),7.60(d,J＝6.6Hz,3H),7.52-7.48(m,2H),7.46(s,2H),5.18-5.10(m,1H),4.50-4.41(m,3H),4.33(d,J＝17.4Hz,1H),3.00-2.86(m,1H),2.61(d,J＝17.2Hz,1H),2.46-2.35(m,1H),2.08-1.94(m,1H). ¹³ C NMR(101 MHz,DMSO)δ173.33,171.44,168.32,152.85,143.25,142.86,132.74,132.54,130.97,130.73,130.69,129.38,129.32,127.65,123.47,122.68,120.27,120.13,84.18,84.05,52.00,47.56,42.91,31.61,22.90.

4-benzoyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzamide(18). ¹ H NMR(400 MHz,DMSO)δ11.01(s,1H),9.48(t,J＝5.9Hz,1H),8.10(d,J＝8.3Hz,2H),7.83(d,J＝8.3Hz,2H),7.79-7.75(m,2H),7.71(d,J＝7.5Hz,2H),7.58(dd,J＝10.5,4.7Hz,3H),7.51(d,J＝7.9Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.64(d,J＝5.8Hz,2H),4.46(d,J＝17.4Hz,1H),4.32(d,J＝17.4Hz,1H),2.98-2.88(m,1H),2.60(dd,J＝15.4,2.0Hz,1H),2.46-2.34(m,1H),2.01(dd,J＝9.0,3.5Hz,1H). ¹³ C NMR(101 MHz,DMSO)δ195.84,173.33,171.45,168.38,165.98,144.15,142.83,139.69,137.86,137.04,133.45,130.83,130.13,129.96,129.09,127.94,127.55,123.40,122.57,51.99,47.55,43.26,31.61,22.91.

3-([1,1'-biphenyl]-4-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)propiolamide(19). ¹ H NMR(400 MHz,DMSO)δ11.01(s,1H),9.47(t,J＝5.8Hz,1H),7.90-7.66(m,7H),7.56-7.37(m,5H),5.13(dd,J＝13.2,4.9Hz,1H),4.70-4.42(m,3H),4.33(d,J＝17.4Hz,1H),2.99-2.86(m,1H),2.61(d,J＝16.4Hz,1H),2.47-2.34(m,1H),2.07-1.95(m,1H). ¹³ C NMR(101 MHz,DMSO)δ173.32,171.44,168.30,152.86,143.23,142.88,142.15,139.21,133.19,131.01,129.51,128.64,127.67,127.54,127.20,123.50,122.70,119.06,84.84,83.99,52.00,47.54,42.94,31.61,22.90.

4-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)picolinamide(20). ¹ H NMR(400 MHz,DMSO)δ11.00(s,1H),9.59(t,J＝6.2Hz,1H),8.65(d,J＝5.2 Hz,1H),8.05(d,J＝1.7Hz,1H),7.78(dd,J＝5.2,2.0Hz,1H),7.69(d,J＝7.8Hz,1H),7.54(s,1H),7.47(d,J＝7.8Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.62(d,J＝6.2Hz,2H),4.43(d,J＝17.3Hz,1H),4.30(d,J＝17.3Hz,1H),3.00-2.87(m,1H),2.60(d,J＝16.8Hz,1H),2.38(qd,J＝13.1,4.2Hz,1H),2.00(d,J＝7.7Hz,1H). ¹³ C NMR(101MHz,DMSO)δ173.31,171.43,168.35,163.38,152.01,150.53,144.99,143.95,142.76,130.81,127.63,126.96,123.35,122.62,122.55,51.97,47.51,43.04,31.61,22.90.

comparative example 1

Paper J Med chem.2021,64 (4): 1835-1843.Doi:10.1021/acs. Jmed chem.0c01489. Title: CC-90009:A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia. The discovery process of CC-90009 is reported as follows:

this compound has been commercialized and purchased directly from InvivoChem corporation (CAS number: 1860875-51-9).

Product effect test

1. Degradation of BRD4 and GSPT1 proteins (Western blot method)

1. Cell culture: THP-1 cell culture medium is RMPI1640+10% FBS+1% penicillin streptomycin solution, and the cells are all at 37 ℃ and 5% CO ₂ Culturing under the condition.

2. And (3) paving: 2ml of 1X 10 density was added to each well of a 6-well plate one day in advance ⁶ Cells were cultured overnight at a cell density of 2X 10 the next day per ml ⁶ 1 mu M concentration of the test compound solution was added to each well at a rate of one volume/ml, and the mixture was placed at 37℃with 5% CO ₂ Culturing in incubator for 24 hr.

3. Extraction of cellular proteins

(1) Mixing the RIPA lysate and the protease inhibitor.

(2) Cells were centrifuged to discard the medium, resuspended in PBS, centrifuged, and pellet was left.

(3) RIPA mix lysate was added per well based on cell mass, and transferred to 1.5ml EP tube after blow-down.

(4) The 1.5ml EP tube was placed on ice for 10min and centrifuged at 12000g for 10min at 4℃and the protein supernatant was transferred to a fresh 1.5ml EP tube.

Determination of total protein concentration by Bradford

(1) The supernatant was diluted 20-fold and 3. Mu.l of the dilution+100. Mu.l of Bradford were taken into a new tube.

(2) Mixing, taking 90 μl into 96-well plate, and standing for 5min.

(3) The absorbance was measured by an ultraviolet spectrophotometer at a wavelength of 595nm.

SDS-polyacrylamide gel electrophoresis

(1) Protein sample is added with SDS loading buffer and denatured for 5min at 95 ℃.

(2) The comb was carefully removed, the glass plate impregnated with SDS-PAGE gel was mounted on an electrophoresis rack with the short plate facing inward, and placed in an electrophoresis tank, and 1 XTris-Gly electrophoresis buffer pre-cooled overnight at 4℃was poured into the electrophoresis tank.

(3) Protein samples were added to each lane according to the equal mass and equal volume principle, 3. Mu.l protein markers were added to both sides, and an equal volume of 1×loading buffer was added to the no sample lane. The loading amount of each well is 15-20 μl.

(4) Covering the electrophoresis tank cover, switching on the power supply, performing constant voltage electrophoresis at 80V for 20-30min, pressing the protein sample into a line, increasing the voltage to 120V for electrophoresis for about 40-60min, and continuing electrophoresis until bromophenol blue reaches the bottom of the separation gel.

6. Transfer film

(1) Preparing sponge, filter paper and PVDF membrane, pouring 1X transfer buffer solution and methanol which are pre-cooled overnight at 4 ℃ into a enamel tray respectively, soaking the PVDF membrane in methanol for 10min for activation, and fully soaking the sponge and the filter paper in the transfer buffer solution.

(2) And (3) taking the glass plates out of the electrophoresis tank, separating the two layers of glass plates, cutting off concentrated gel, cutting off redundant separation gel according to the size of target protein, and placing the separated gel in a transfer film liquid.

(3) The films are placed in a transfer fixer according to the sequence of the black glue and the white film, and each layer is placed, bubbles are gently removed, and the PVDF film is marked. The clamp is clamped and then is placed in the transfer electrophoresis tank, and the black surface is opposite to the black surface. Pouring transfer buffer solution, and covering with a cover.

(4) The transfer tank was placed in a foam box filled with crushed ice. And (5) switching on a power supply, and performing constant current transfer for 60 minutes at 260-280 mA.

7. Immunostaining

(1) Closure

1) 5% skimmed milk powder is prepared, and poured into an incubation box after being fully and uniformly mixed.

2) And taking out the PVDF membrane after membrane transfer, rinsing the PVDF membrane once by TBST to remove salt, putting the PVDF membrane into an incubation box filled with 5% skimmed milk powder, and slowly shaking and sealing the PVDF membrane on a shaking table for 1h.

(2) Target proteins react with primary antibodies (BRD 4 and GSPT 1):

1) Preparing an anti-reaction liquid: preparing a 15ml centrifuge tube, adding 3ml primary antibody diluent, adding the primary antibody according to the dilution ratio marked by the antibody specification, reversing and uniformly mixing, and placing on ice.

2) PVDF membrane is transferred from the sealing liquid to TBST, and strips are cut according to the molecular weight of target protein.

3) The strips were placed in a centrifuge tube containing primary antibody, and incubated overnight with shaking at 4 ℃.

(3) Reaction of the antibody with HRP-labeled secondary antibody:

1) TBST was washed 3 times for 10min each.

2) Preparing a secondary antibody reaction solution: prepare a 15ml centrifuge tube, add 3ml 5% skim milk powder, add goat anti-rabbit IgG-HRP (1:5000) or goat anti-mouse IgG-HRP (1:5000), mix upside down.

3) The strips were placed in a plastic box containing secondary antibody reaction solution and incubated for 1h at room temperature with shaking.

(4) Exposure:

1) TBST was washed 3 times for 10min each.

2) The solution A and the solution B are mixed in equal volume to prepare the developing solution and are protected from light.

3) Placing the strip in a black glue plate, wiping off excessive water, dripping a color development liquid to fully cover the strip, and exposing and developing color.

Remarks: the development results were subjected to gray scale analysis using Image J, and degradation ratios were obtained by normalization, wherein degradation effects of the compounds of the present application at a concentration of between 1 μm are shown in table 1. With respect to the effect of the degradation, wherein "+++ +". "means degradation the effect is between 100% and 80%; "+++". Representation of degradation effect between 80% and 60%; "++" indicates that the degradation effect is between 60% and 30%; "+" indicates that the degradation effect is between 30% and 10%; "" indicates that the degradation effect is less than 10%.

Table 1 results of degradation test of each compound on BRD4 and GSPT1

As shown in Table 1, the partial compounds of the invention have remarkable degradation effects on BDR4 and GSPT1 proteins, and the effect is superior to that of clinical medicine CC-90009.

2. Proliferation inhibitory Activity against NHL and AML tumor cells

Reagents and consumables, sterile DMSO, cell culture medium (RMPI 1640+10% FBS+1% penicillin streptomycin solution), 200ul of 8 or 12 row tubes, 0.2ml PCR tubes, 12 row gun, small yellow plate, 10ul and 200ul pipettes, 96 well cell culture plate, 1.5ml EP tube.

Reagents and consumables, sterile DMSO, cell culture medium (RMPI 1640+10% FBS+1% penicillin streptomycin solution), 200. Mu.l of 8 or 12 row tubes, 0.2ml PCR tubes, 12 row guns, small yellow plates, 10. Mu.l and 200. Mu.l pipettes, 96 well cell culture plates, 1.5ml EP tubes.

Core elements: the cell density is 1-2×10 ⁶ Per ml, handling with a tube, cell count, single Kong Xibao of approximately 10000 cells, were gently mixed 2 times with a 1ml pipette to fully re-suspend before cell dispensing.

The experimental steps are as follows:

1. the cells were transferred the day before the experiment to a second day density of 1-2×10 ⁶ In the case of yellowing of the medium, it is necessary to count the cells and centrifuge the cells, while adjusting the concentration to 1X 10 ⁶ About/ml;

2. preparing 30-100mM mother liquor into 5mM stock solution (total volume is greater than 50 μl, then split charging into 0.2ml PCR tubes, 10 μl each tube, storing at-80 or-20deg.C), and temporarily storing the rest split charging stock solution at 4deg.C for short term storage;

3. taking 2 mu l of 5mM storage solution, adding the storage solution into 198 mu l of complete culture medium, and flicking for 20 times after the cover is marked, and uniformly mixing to obtain 50 mu M temporary liquid;

4. diluting with 50 μm medicine within 100 times to obtain maximum working concentration 1 (conventional 0.5-10 μm) with volume not lower than 250 μl;

5. the small yellow plates are placed in order to form 12 rows of tubes, and each drug needs to be provided with 9 gradients of different concentrations (5 times dilution for initial experiments and then readjustment, 3 times dilution for formal experiments) and 1 control hole without drug. The following is an example at 3-fold dilution;

6. transfer 240 μl of working concentration 1 (note that drug concentration is 2 times the actual working concentration because equal volumes of cells are added) into the first column of the row of tubes, and the remaining wells are filled with 160 μl of complete medium with a row gun;

7. adding 80 μl of working solution 1 into the latter hole, mixing thoroughly with a pipettor for about 10 times, adding 80 μl into the latter hole, and so on to obtain a series of diluted medicines;

8. transferring 50 μl of diluted medicines into 96-well culture plates, and parallelizing each medicine for 3 times;

9. culturing cells for cell count at a density of 1-2×10 ⁶ Preferably/ml, followed by dilution of the cell density to 2X 10 with complete medium ⁵ Per ml (10000 cells per well eventually), the total volume is calculated according to the total number of drugs to be developed, taking care to leave a sufficient margin;

10. transferring cells into a liquid separating tank, lightly mixing the cells for 2 times by a 1ml liquid transferring device, immediately transferring 50 mu l of cell suspension into a culture plate added with medicines by using a row gun, and lightly rotating the culture plate for uniform mixing after all single plates are added;

mixing the cells with a 11.1ml pipette for 2 times, immediately adding the cells into the subsequent culture plate by using a row gun, slightly rotating the culture plate, mixing uniformly, and placing the culture plate into an incubator for culturing the cells for 3 days;

CCK8 detection was performed 12.3 days later, and analytical calculations were performed using Graphpad Prism software. Inhibition ratio = (100-OD _{Sample of} /OD _Solvent(s) ) X 100%, where OD _{Sample of} For absorbance values detected after addition of each concentration of the test substance, OD _Solvent(s) Absorbance values detected for vehicle group (vehicle added, no test substance added). The positive control was CC-90009. The results of the cytotoxicity test of each compound against NHL and AML tumor cells are shown in table 2.

Remarks: IC (integrated circuit) ₅₀ : concentration of Compounds inhibiting tumor cell growth by 50%

IC ₅₀ The size is divided into four layers:

“++++”,IC ₅₀ <200nM；“+++”,IC ₅₀ 200-2000nM; "++", IC ₅₀ 2000-4000nM; "-" means IC ₅₀ >4000nM。

Table 2 results of cytotoxicity test of Compounds against NHL and AML tumor cells

From Table 2, the compounds of the invention can obviously inhibit the growth of different NHL and AML tumor cell lines, wherein part of the compounds have obvious inhibition effect on the NHL and AML tumor cell lines, and the effect is better than that of clinical medicine CC-90009.

3. Acute Myeloid Leukemia (AML) apoptosis prevention experiment

1. Drug configuration: the stock solution of the drug was 10mM, and 10-fold dilution was performed using DMSO to prepare a 2-8 gradient stock solution of 1mM, 0.1mM, 0.01mM, and 0.001 mM.

2. 5mL bone marrow of a tumor patient (note: signed patient informed consent and obtained medical ethical examination lot) is collected, single nuclear cells of the patient are separated by centrifugation of Ficoll separating liquid, physiological saline is used for washing for 2 times, and cell concentration is adjusted to prepare cell suspension with the concentration of 200 ten thousand cells/mL.

3. Inoculating 20 ten thousand cells/hole of the cell suspension prepared in the step 2 into a 12-hole plate for culturing, wherein the culture medium is DMEM (medium-cell management) and is purchased from Thermo company; the culture temperature was 37℃and the culture volume was 1mL.

4. Treatment wells were treated with different concentrations of drug stock solution (1:1000 dilution), control groups were added with equal volumes of DMSO, mixed well, and flow cytometry was used to detect the ratio of leukemic cells to apoptosis at 48 hours, and experimental results are shown in table 3.

The proportion of apoptosis is divided into layers:

"+". "+", apoptosis ratio >60%; "++",60% > -apoptosis ratio >40%; "+"40% > -apoptosis ratio >20%; "-" indicates that the proportion of apoptosis is <20%.

Table 3 results of apoptosis test of Compounds on acute myeloid leukemia

As shown in table 3, compound 19 can significantly promote apoptosis of tumor cells of patients with acute myeloid leukemia, and has significant curative effect.

All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims

1. An amide compound is characterized by having a molecular structure represented by the following formula (I):

wherein A is selected from-CH ₂ -、X is selected from-CH-, -NH-; l is selected from-> B is selected from->R ₁ Selected from H, amino, hydroxy, cyano, halogen; r is R ₂ Selected from H, amino, hydroxy, cyano, halogen.

2. An amide compound according to claim 1, characterized by having any one of the following formulas la or lb:

wherein X is selected from-CH-, -NH-; l is selected from B is selected fromR ₁ Selected from H, amino, hydroxy, cyano, halogen; r is R ₂ Selected from H, amino, hydroxy, cyano, halogen.

3. An amide compound according to claim 2, which has a structural formula as shown in any one of the following formulas 1 to 20:

4. a process for producing an amide-based compound according to any one of claims 1 to 3, comprising the steps of:

wherein X is selected from-CH-, -NH-; l is selected from B is selected fromR ₁ Selected from H, amino, hydroxy, cyano, halogen; r is R ₂ Selected from H, amino, hydroxy, cyano, halogen, n is equal to 1 or 2.

5. The process according to claim 4, wherein the condensation reaction is carried out at a temperature of 20 to 30℃for a period of 0.5 to 3 hours, wherein the amount of 4- (4, 6-dimethoxytriazin-2-yl) -4-methylmorpholinium chloride is 1.5 equivalents, the amount of azomethylmorpholine is 2 equivalents, and the solvent is DMF.

6. A pharmaceutical composition characterized by: the pharmaceutical composition comprising a compound of any one of claim 13 or a pharmaceutically acceptable salt thereof.

7. Use of a compound according to any one of claims 13 for the preparation of BRD4 degrading agents.

8. Use of a compound according to any one of claims 13 for the preparation of a GSPT1 degrading agent.

9. Use of a compound according to any one of claims 1-2 for the manufacture of a medicament for the treatment of a neoplastic disease associated with BRD4 and GSPT1 targets.

10. The use according to claim 9, characterized in that: the tumor diseases comprise non-Hodgkin lymphoma, chronic lymphocytic leukemia, B-cell lymphoma, mantle cell lymphoma and acute myelogenous leukemia.